Abstract—The pathological role of interferon- (IFN-) in atherosclerosis is mediated through effects on macrophages, foam cells, and other vascular cells. Recently, we reported that ABC1 message and protein levels were decreased 3- to 4-fold in foam cells by IFN-. In the present study, the pathway by which IFN- inhibited ABC1 expression was investigated with Stat1 knockout mice. IFN---stimulated, wild-type, macrophage-derived foam cells, as previously reported, exhibited a decrease in cholesterol efflux and ABC1 expression as well as an increase in acyl coenzyme A:cholesterol-O-acyltransferase activity. However, IFN- treatment of foam cells from Stat1 knockout mice failed to demonstrate reductions in efflux or ABC1 expression at the message or protein levels, nor were there any increases in acyl coenzyme A:cholesterol-O-acyltransferase activity. However, ABC1 mRNA expression in macrophages from Stat1 knockout mice could still be demonstrated to be increased by lipid loading with acetylated low density lipoprotein. Finally, Stat1-independent gene activation by IFN- was intact in the Stat1 KO macrophages, inasmuch as IFN- was shown to stimulate increases in interleukin-6 production in the Stat1 KO macrophages that were comparable to those observed in the wild-type macrophages. Therefore, Stat1 signaling is necessary and sufficient for the inhibitory effects of IFN- on cholesterol efflux and ABC1 expression.